Abstract

PURPOSE:

Optic nerve aplasia (ONA, OMIM 165550) is a very rare unilateral or bilateral condition that leads to blindness in the affected eye, and is usually associated with other ocular abnormalities. Although bilateral ONA often occurs in association with severe congenital anomalies of the brain, nonsyndromic sporadic forms with bilateral ONA have been described. So far, no autosomal-dominant nonsyndromic ONA has been reported. The genetic basis of this condition remains largely unknown, as no developmental genes other than paired box gene 6 (PAX6) are known to be implicated in sporadic bilateral ONA.

METHODS:

The individuals reported underwent extensive ophthalmological, endocrinological, and neurologic evaluation, including neuroimaging of the visual pathways. In addition genomewide copy number screening was performed.

RESULTS:

Here we report an autosomal-dominant form of nonsyndromic ONA in a Belgian pedigree, with unilateral microphthalmia and ONA in the second generation (II:1), and bilateral ONA in two sibs of the third generation (III:1; III:2). No PAX6 mutation was found. Genome wide copy number screening revealed a microdeletion of maximal 363 kb of chromosome 10q23.33q23.33 in all affected individuals (II:1, III:1; III:2) and in unaffected I:1, containing three genes: exocyst complex component 6 (EXOC6), cytochrome p450, subfamily XXVIA, polypeptide 1 (CYP26A1), and cytochrome p450, subfamily XXVIC, polypeptide 1 (CYP26C1). The latter two encode retinoic acid-degrading enzymes.

CONCLUSIONS:

This is the first study reporting an autosomal-dominant form of nonsyndromic ONA. The diagnostic value of neuroimaging in uncovering ONA in microphthalmic patients is demonstrated. Although involvement of other genetic factors cannot be ruled out, our study might point to a role of CYP26A1 and CYP26C1 in the pathogenesis of nonsyndromic ONA.

Clinical pictures of III:2, III:1 and II:1. A: A picture of III:2 with mild bilateral microphthalmia with 10.5 mm corneal diameters and atypical coloboma of the iris in the right eye. B: A picture of twin brother III:1 with bilateral microphthalmia with 9 mm corneal diameters and scleralization of the inferior cornea. C-D: Fundus picture of III:1 showing the absence of the optic nerve, dysplastic retinae, and a few retinal vessels. E: A picture of the father’s (II:1) left eye, showing unilateral left microphthalmos (corneal diameter of 7 mm) with a vascularized cornea, impairing the view to the anterior segment and to the fundus.

Ultrasound and MRI findings in III:1 and II:1. The father’s (II:1) Doppler ultrasonographic examination. This demonstrates A: a normal right eye with the optic nerve and arteria centralis retinae; B: a left microphthalmic heterogeneous eye without the optic nerve visible. C, D: The son’s (III:1) Doppler ultrasonographic examination demonstrating the absence of both optic nerves and corresponding vascularization, but the presence of posterior ciliary vessels (C and D for right and left eye, respectively). The vessels are represented in color. The Doppler examination is represented in the boxes. E: II:1’s axial T2-weighted image in MRI demonstrated a normal right eye and lens and a left microphthalmic eye with thick sclera. F: III:1’s axial T2-weighted image in MRI showed an almost normal morphology of both eyes but the absence of optic nerves (with some remnants of dural sheath), chiasms, and tracts. G-H: Coronal T1-weighted MRI images in the midorbital (G) and intracranial (H) planes. This shows the complete lack of both orbital nerves in the son, III:1.